Abstract: Work in genetic model organisms has connected genes to behavior. Electrophysiology in awake, behaving animals has associated neuronal activity with cognition and action. This proposal lies at the interface of these two fields. We aim to reveal how genes, through their effects on cellular electrophysiology, influence higher brain function and behavior. We focus on a specific higher function, decision-making: the mental process that precedes and ultimately yields a behavioral choice. A healthy brain allows for choices that are adaptive and flexible. In drug addiction and mental illnesses such as depression, obsessive-compulsive disorder, and schizophrenia, behavioral choices are maladaptive, stereotypical, and repetitive. A deeper understanding of decision processes could improve the health of many. We propose to study decision-making in the fruit fly, Drosophila melanogaster, where there is a unique opportunity to form cross-disciplinary insights. We will use a new apparatus that allows us, for the first time, to record electrophysiological signals from genetically identified neurons in activly behaving fruit flies. Drosophila will perform simple choice tasks, like deciding to turn left or riht in response to visual stimuli. We will record and manipulate neuronal activity while the flies make up their mind or change their mind. After recordings, we will sequence RNA extracted from cells that govern decision-making to determine whether variability in their electrophysiological output, and variability in fly behavior, can be explained by the expression level of genes that regulate membrane and synaptic physiology. Drosophila offers a unique platform for this research program because behavioral paradigms, cell- type-specific genetic tools, and behavioral-physiology methods are mature. The work aims to reveal how genes, through their effect on cellular electrophysiology, influence decision-making, ultimately providing a foundation for more rational drug design for human mental illness. Public Health Relevance: A better understanding of how brains make choices could help modify risky behaviors that lead to HIV infection and drug addiction, which are major public health concerns. By providing a deeper understanding of decision-making circuits, the proposed work can ultimately yield insight into treatments for a variety of mental illnesses, such as depression, one of the leading causes of disability in the world.